Kathryn L Penney1, Barbara L Banbury2, Stephanie Bien2, Tabitha A Harrison2, Xinwei Hua3, Amanda I Phipps3, Wei Sun2, Mingyang Song4, Amit D Joshi5, Steven R Alberts6, Carmen J Allegra7, James Atkins8, Linda H Colangelo9, Thomas J George7, Richard M Goldberg10, Peter C Lucas9, Suresh G Nair11, Qian Shi12, Frank A Sinicrope6, Norman Wolmark13, Greg Yothers9, Ulrike Peters3, Polly A Newcomb3, Andrew T Chan14. 1. Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts. 2. Fred Hutchinson Cancer Research Center, Seattle, Washington. 3. Fred Hutchinson Cancer Research Center, Seattle, Washington; University of Washington, Seattle, Washington. 4. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts; Clinical and Translational Epidemiology Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts; Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts. 5. Clinical and Translational Epidemiology Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts. 6. Department of Health Science Research, Mayo Clinic, Rochester, Minnesota. 7. University of Florida, Gainesville, Florida; NRG Oncology, Pittsburgh, Pennsylvania. 8. NRG Oncology, Pittsburgh, Pennsylvania; Southeast Clinical Oncology Research (SCOR) Consortium NCORP, Winston-Salem, North Carolina. 9. NRG Oncology, Pittsburgh, Pennsylvania; University of Pittsburgh, Pittsburgh, Pennsylvania. 10. NRG Oncology, Pittsburgh, Pennsylvania; West Virginia University Cancer Institute, Morgantown, West Virginia. 11. Lehigh Valley Hospital-Cedar Crest, Allentown, Pennsylvania. 12. Department of Health Science Research, Mayo Clinic, Rochester, Minnesota; Alliance Statistics and Data Center, Mayo Clinic, Rochester, Minnesota. 13. NRG Oncology, Pittsburgh, Pennsylvania; Allegheny Health Network Cancer Institute, Pittsburgh, Pennsylvania. 14. Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts; Clinical and Translational Epidemiology Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts; Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts. Electronic address: achan@mgh.harvard.edu.
Abstract
BACKGROUND & AIMS: Many genetic variants have been associated with colorectal cancer risk, although few have been associated with survival times of patients. Identification of genetic variants associated with survival times might improve our understanding of disease progression and aid in outcome prediction. We performed a genome-wide association study to identify variants associated with colon cancer survival time. METHODS: We performed a post hoc analysis of data from NCCTG N0147 (Alliance), a randomized phase 3 trial of patients with resected stage III colon cancer, and from NSABP C-08 (NRG), a phase 3 trial that compared therapy regimens for patients with resected stage II or III colon cancer. Genotype analyses were performed on DNA from blood samples from 4974 patients. We used Cox proportional hazards regression to evaluate the association of each single nucleotide polymorphism with times of overall survival and disease-free survival, adjusting for age at diagnosis, sex, treatment group, and principal components of genetic ancestry. We performed the analysis for studies N0147 and C-08 separately, and results were combined in a fixed-effects meta-analysis. RESULTS: A locus on chromosome 7p15.2 was significantly associated with overall survival time (P ≤ 5x10-08). The most significant variant at this locus, rs76766811 (P = 1.6x10-08), is common among African Americans (minor allele frequency, approximately 18%) but rare in European Americans (minor allele frequency <0.1%). Within strata of self-reported ancestry, this variant was associated with times of overall survival and disease-free survival in only African Americans (hazard ratio for overall survival, 2.82; 95% CI, 1.88-4.23; P = 5.0x10-07 and hazard ratio for disease-free survival, 2.27; 95% CI, 1.62-3.18; P = 1.8x10-06). CONCLUSIONS: In an analysis of data from 2 trials of patients with stage II or III colon cancer, we identified rs76766811 as a potential prognostic variant in African American patients. This finding should be confirmed in additional study populations. ClinicalTrials.gov Identifiers: NCT00096278 (NSABP C-08) and NCT00079274 (NCCTG N0147).
BACKGROUND & AIMS: Many genetic variants have been associated with colorectal cancer risk, although few have been associated with survival times of patients. Identification of genetic variants associated with survival times might improve our understanding of disease progression and aid in outcome prediction. We performed a genome-wide association study to identify variants associated with colon cancer survival time. METHODS: We performed a post hoc analysis of data from NCCTG N0147 (Alliance), a randomized phase 3 trial of patients with resected stage III colon cancer, and from NSABP C-08 (NRG), a phase 3 trial that compared therapy regimens for patients with resected stage II or III colon cancer. Genotype analyses were performed on DNA from blood samples from 4974 patients. We used Cox proportional hazards regression to evaluate the association of each single nucleotide polymorphism with times of overall survival and disease-free survival, adjusting for age at diagnosis, sex, treatment group, and principal components of genetic ancestry. We performed the analysis for studies N0147 and C-08 separately, and results were combined in a fixed-effects meta-analysis. RESULTS: A locus on chromosome 7p15.2 was significantly associated with overall survival time (P ≤ 5x10-08). The most significant variant at this locus, rs76766811 (P = 1.6x10-08), is common among African Americans (minor allele frequency, approximately 18%) but rare in European Americans (minor allele frequency <0.1%). Within strata of self-reported ancestry, this variant was associated with times of overall survival and disease-free survival in only African Americans (hazard ratio for overall survival, 2.82; 95% CI, 1.88-4.23; P = 5.0x10-07 and hazard ratio for disease-free survival, 2.27; 95% CI, 1.62-3.18; P = 1.8x10-06). CONCLUSIONS: In an analysis of data from 2 trials of patients with stage II or III colon cancer, we identified rs76766811 as a potential prognostic variant in African American patients. This finding should be confirmed in additional study populations. ClinicalTrials.gov Identifiers: NCT00096278 (NSABP C-08) and NCT00079274 (NCCTG N0147).
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